Metformin has been shown to bring about major alterations in expression profiles in multiple different tissues in the body, with accompanying changes in disease course and disease risk. The altered expression profile brings about a "backshift" in the expression profile, converting the expression profile in an older or higher risk individual into an expression profile more closely resembling that of a younger or lower risk individual. This type of back shifting effect has been observed in multiple different systems, and agents that have this effect are considered long term caloric restriction (LTCR) mimetics since the initial system in which this phenomenon was observed was the caloric restriction mouse model of longevity extension. It remains unknown whether metformin can serve as an LTCR mimetic in the eye. We have preliminary data showing reduced risk of primary open-angle glaucoma (POAG) in diabetics taking metformin, as compared with diabetics who are not on metformin, and we have preliminary evidence of age-associated expression profile changes in trabecular meshwork (TM). We propose an initial look at whether metformin might be affecting systems in the eye that are not a direct result of diabetes through two approaches. 1) We will do expression profiling in optic nerve and TM samples from diabetic individuals using metformin and diabetic individuals who are not using metformin, and use quantitative PCR to validate these results in RNA samples from optic nerve, TM, and trabeculectomy surgical samples, and 2) we will carry out a more extensive analysis of data on metformin affects on glaucoma risk through analysis of a very large health services database containing health care claims information on 8.3 million covered lives. The results of this study will provide initial information regarding whether metformin is altering gene expression in ocular tissues of importance to a disease phenotype that shows reduced risk in response to metformin, and will better quantify and characterize glaucoma risk reduction in response to metformin. Data from this proof-of- principle project will form the basis for experimental design of an R01 proposal to examine metformin effects on a more extensive basis relative to multiple different ocular tissues and diseases. This project will help define metformin as a new tool for the study of factors affecting glaucoma risk and offers an important breakthrough regarding ocular impact of a drug that is used extensively in the treatment of diabetes. PUBLIC HEALTH RELEVANCE: Metformin has been shown to alter disease risk, and to alter gene expression in multiple non-ocular cell types in the body. Our preliminary evidence of metformin effects on risk of primary open-angle glaucoma suggests the need to evaluate whether metformin is affecting gene expression in ocular tissues relevant to glaucoma pathology and to further quantify and characterize the glaucoma risk reduction. This project will use RNA samples from optic nerve, trabecular meshwork, and trabeculectomy surgical samples from diabetics who are, or are not taking Metformin, to determine whether the drug is affecting gene expression and will use a very large database of health services information to determine whether metformin is affecting disease risk.